Italian Prostate Biopsies Group: 2016 Updated Guidelines Insights

Discussion

The major issues discussed by the panel are discussed in the following sections.

1 Indication for Prostate Biopsy

Recommendation 1: A prostatic biopsy is strongly recommended with a

• PSA >10 ng/ml

• Positive digital rectal examination (DRE)

• mpMRI Prostate Imaging Reporting and Data System (PIRADS) ≥4 (even if not recommended in biopsy-naive patients).

The need for prostate biopsy is based on prostate-specific antigen level (PSA) with or without suspicious DRE (6). PSA testing should be offered to patients following detailed counseling on the potential risks and benefits. Moreover, an individualized risk-adapted strategy for early detection of PCa should be performed for those with life expectancy >10-15 years, comorbidity, family history of PCa, Afro-American race (PSA evaluation starting from 45 years of age). Data in the literature indicate that age alone is not but rather comorbidities are the major factors that should be considered when performing a biopsy to detect PCa (7-9). It seems necessary to consider patient age and comorbidities with the use of validated instruments such as the Charlson comorbidity index (CCI) to assess life expectancy. CCI has been validated in men with PCa and has been shown to have a relatively high predictive accuracy that can be used in daily routine. The current guidelines on the diagnosis of PCa recommend PSA testing in men who have a life expectancy >10 years and to consider comorbidities and fragilities before performing a biopsy (7-9).

Limited PSA elevation alone should not prompt immediate biopsy (6). The PSA level should be verified after a few weeks using the same assay under standardized conditions (i.e. no ejaculation, manipulation, or urinary tract infection) in the laboratory using the same testing standard (11). Empiric use of antibiotics in an asymptomatic patient in order to lower the PSA level should not be undertaken even if it is common in current clinical practice (11).

PSA should be considered as a continuous parameter (12). The higher the value, the more likely is the existence of PCa. However, a value of >4 ng/ml according to Hybritech standard (Beckman Coulter, USA) is still a recommendation for performing prostate biopsy. In our review, we considered the Hybritech as standard calibration since it has been the clinical standard used for biopsy recommendations since 1994, the beginning of PSA screening. If the laboratory test used the World Health Organization (WHO) criteria (13) we should consider PSA >3 ng/ml as cut-off for a recommendation to perform prostate biopsy. In young men with a family history of prostate cancer, the cut-off level should be established at 2.5 ng/ml (2).

Even if the free/total PSA ratio (%FPSA) has been demonstrated to reduce the number of unnecessary biopsies, %FPSA (cut-off of 25%) in men with PSA between 2.5 and 10 ng/ml has demonstrated low overall diagnostic accuracy (14). Thus, %FPSA usage should be considered optional in the evaluation of patients for an initial biopsy. Since the probability of finding PCa with a value of %FPSA <10% is relatively high, this cut-off value has remained an indication to perform a biopsy, as shown in the previous guidelines (2).

Several studies have shown that men with PSA density >0.15 ng/ml are significantly more likely to have PCa, but the level of evidence is low (15-17).

This indication has not changed according to the 2007 guidelines. Moreover, PSA velocity and doubling time are of limited value in supporting indications for biopsy due to several unsolved issues. Prospective studies have not shown that these measurements can provide additional information compared with use of PSA alone (18). No change has been performed comparing with the 2007 guidelines. The use of risk calculators including more clinical parameters have provided good accuracy and could be offered for men with PSA values between 2.5 and 10 ng/ml. Nevertheless, no studies have confirmed the real utility or improvement in the diagnostic process in that clinical setting. Thus, both these parameters are considered optional in the decision-making (19).

Although DRE has a low sensitivity in diagnosing PCa, the presence of an abnormal DRE is associated with an increased risk of PCa with a high Gleason score. A positive DRE remains a strong indication to perform a biopsy independently of the PSA value (2).

Prostate biopsy should be performed if there is suspicion for PCa and if the treatment decision might be changed by PCa diagnosis (patients eligible for surgery for benign prostatic hyperplasia).

The most controversial topic discussed by the Committee was the role of mpMRI in the initial setting. mpMRI has recently gained growing importance in the diagnosis of clinically significant PCa. The estimated mpMRI sensitivity and specificity for PCa detection varies between 57% and 100% vs. 44% and 96%, respectively (20-23).

Nowadays, it is advisable to use mpMRI targeted biopsy (TPBx) since it has the potential to reduce the sampling error through localization of disease, increasing the clinically significant PCa detection (24-28). The high negative predictive value of mpMRI is important because it can be used to rule-out significant disease. This may result in fewer or even no biopsies in patients with PSA suspicious for PCa but a negative mpMRI. Moreover, the PIRADS score used to convey the degree of suspicion on mpMRI seems to be the strongest predictor of the presence of clinically significant PCa (24-28).

Nevertheless, the role of mpMRI in the initial setting in the literature is controversial. In general, the results of the mpMRI in PCa detection differs among various series; a recent meta-analysis showed a pooled sensitivity of 0.74 [95% confidence interval (CI)=0.66-0.81], specificity of 0.88 (95% CI=0.82-0.92), negative predictive value ranged from 0.65 to 0.94 and positive predictive value from 0.31 to 0.95, for detection of clinically significant PCa (GS ≥7; volume ≥0.5 cc) (29). The PIRADS categories 4 and 5 are associated with high probability of the presence of clinically significant PCa, while the percentage of such PCa in the PIRADS 3 category is variable from 15% to 29%. Rarely, small foci of csPCa can be present even in PIRADS 1 and 2 categories, but usually tumor missed at mpMRI represents indolent disease (30-32).

There are few studies on this topic. Mozer et al. reported the outcomes of comparing TPBx with extended 12-core systematic biopsy (SPBx) in men with no previous biopsies. In a cohort of 152 men, overall cancer detection was lower for TPBx than for SPBx (54% vs. 57%). There was almost no difference in the detection of Gleason score 7 or higher between the two techniques in their biopsy results (21.7% vs. 22.4%). However, when categorized as clinically significant disease vs. clinically insignificant disease, TPBx detected more significant cancers than did SPBx (43.4% vs. 36.8%) (33).

Delongchamps et al. also reported outcomes of pre-biopsy mpMRI and TPBx vs. SPBx in 391 men who presented for the first biopsy. TPBx demonstrated higher Gleason score 7 and overall PCa detection than SPBx. In these two groups, but not in the visual co-registration group, TPBx also yielded higher overall cancer detection than SPBx (34).

Pokorny et al. reported the results of TPBx vs. SPBx in biopsy-naive men. Of 142 men with abnormal mpMRI, defined as a PIRADS score of 3 or greater, PCa was detected by SPBx in 101 (71.1%) vs. 99 (69.7%) by TPBx. However, TPBx detected more high-risk cancer than did standard biopsy (65.5% vs. 52.1%) (22).

Nevertheless, Schoots et al., in a recent meta-analysis, showed that in men with clinical suspicion of PCa and a suspicious lesion observed on mpMRI, TPBx and SPBx did not differ in overall detection of PCa. However, TPBx had a higher rate of detection of clinically significant PCa and a lower rate of detection of insignificant PCa compared to SPBx (29). Subgroup analysis showed that TPBx improved the detection of clinically significant PCa in men with a previous negative biopsy, rather than in men with an initial biopsy. Moreover, in a randomized Finnish clinical trial, addition of mpMRI prior to prostate biopsy, appeared to offer similar diagnostic accuracy compared with routine systematic 12-cores SPBx in the diagnosis of PCa, since similar number of cancer were detected with and without mpMRI (35).

On the contrary, recently, Mendhiratta et al. reported the largest reported cohort of biopsy-naive men undergoing TPBx and SPBx. By yielding a lower rate of overall cancer detection, but a higher rate of Gleason score 7 or greater cancer detection compared to SPBx, their TPBx outcomes reflected the trends reported in other mpMRI-guided prostate biopsy trials. They also demonstrated a significant reduction in low-risk PCa detection with TPBx (36-37).

A great relevance has been given to these results of Mendhiratta et al.: Out of 34 clinically insignificant cancers detected by SPBx and missed by TPBx, 24 (70.1%) were detected in men with PIRADS less than 4 (36-37). They concluded that mpMRI is able to provide added ability to predict the risk of Gleason score 7 or greater PCa, with a negative predictive value of >80% for detecting Gleason score 7 or greater PCa in men with PIRADS ≤3 and a positive predictive value of about 70% in men with a maximum level of suspicious of 4/5. Thus, it may be possible to further optimize the balance between high-grade PCa detection and avoidance of low-risk disease. The authors concluded that pre-biopsy mpMRI followed by TPBx and avoidance of SPBx in select men, especially those with PIRADS 2 or 3, may provide the greatest potential to limit the detection of low-risk cancer while maximizing the detection of high-grade disease.

Based on these observations, the Committee concluded that mpMRI is not mandatory in the initial setting, but when performed, only patients with a PIRADS 4 or 5 should be submitted to prostate biopsy.

2 Indication for re-biopsy

Recommendation 2: A prostatic re-biopsy is strongly recommended with a

• PSA rising above 10 ng/ml

• Positive DRE or DRE modifications

• Inadequate first biopsy set, with or without ASAP finding, with or without multifocal high-grade prostatic intraepithelial neoplasia (HGPIN)

• Positive mpMRI PIRADS ≥3

There is no consensus regarding the need for repeat biopsy in men with previous negative sampling except for those with abnormal histology [i.e., >3 cores with HGPIN, atypical small acinar proliferation (ASAP)], or inadequate initial prostate biopsy and persistence of an elevated PSA level (38).

HGPIN is considered a precursor for PCa development (39, 40). The median risk recorded in the literature for cancer following the diagnosis of isolated HGPIN on needle biopsy is 24.1%, which is not much higher than the risk reported in the literature for a repeat biopsy (39, 40). Current recommendations for isolated HGPIN diagnosis suggest follow-up and the panel was in agreement to consider this approach a strong recommendation. The meaning of multifocal HGPIN is biologically different (41-43); current recommendations for extensive HGPIN (multiple biopsy sites, i.e. ≥3) diagnosis suggest repeating the biopsy within 12 months of the initial biopsy. The Committee is also in agreement to strongly consider re-biopsy in this situation.

ASAP is a diagnosis that occurs in about 1-2% of prostate biopsies (44-47). The term ASAP, first defined by Bostwick, represents suspicious glands without adequate histological atypia for a definitive diagnosis of prostate adenocarcinoma (57). Previous studies have suggested that 17-90% of patients with ASAP have adenocarcinoma present on subsequent prostate biopsies. This would most likely represent under sampling rather than disease progression. Current recommendations (59-66) for ASAP diagnosis suggest repeating the biopsy within 3-6 months of the initial biopsy. The panel of experts has not modified the previous version of guidelines (45-48).

2.1 Prostate cancer markers and indication for re-biopsy. The prostatic cancer gene 3 (PCA3) score which is obtained after massage of the prostate and is measured in the urinary sediment, has been shown to be superior to PSA and the %FPSA in early detection. Univariate analyses have shown that PCA3 and PSA had an Area Under the Curve (AUC) of 0.69-0.76 and 0.68-0.73, respectively, vs. 0.54-0.65 and 0.52-0.58, respectively, in the initial and repeated setting, respectively (49-56). This molecular marker may help in the decision-making process with regard to a repeat biopsy in men with a negative first biopsy but a persistent suspicion of prostate cancer. Unfortunately, no consensus has been reached about the most helpful cut-off. The majority of studies recommend a threshold value of 35 as providing a better balance between sensitivity and specificity. Recently, the literature has compared the cutoff value of 35 with a lower one (e.g. 20), reporting an improvement of the performance of the test. In patients undergoing a repeat biopsy, sensitivity and specificity of 93% and 64%, respectively, have been reported (49-56). On the basis of the quality of the evidence in the literature, the IPBG Committee has therefore stated a very weak recommendation against the use of PCA3 score as an indication for first biopsy, and a weak recommendation in favor of the use of PCA3 score as an indication for a re-biopsy in patients with persistently elevated PSA.

The Prostate Health Index (PHI) represents a mathematical formula that includes −2proPSA, total PSA and free PSA. Different prospective trials showed the superiority of the PHI compared to PSA and PSA derivatives, mainly, at first biopsy. The AUC ROC curve values range between 0.70 and 0.88 for PHI, between 0.50 and 0.53 for PSA and between 0.58 and 0.68 for %FPSA (58-65). The PHI also seems to correlate with biological aggressiveness of cancer, the risk of progression in case of active surveillance, and the tendency to metastasize (58-65). In the case of the first set of biopsies, both in univariate and multivariate analysis, PCA3 was found to provide a better global diagnostic accuracy (AUC 0.71 vs. 0.65), while PHI was a superior predictor of clinically significant PCa, with an AUC of 0.80 vs. 0.55 (58-67). The Committee stated a weak positive recommendation for the use of PHI in the management of the first biopsy; on the other hand it stated a weak recommendation against its use as an indication for a re-biopsy.

2.2 Prostate cancer Imaging and indication for re-biopsy. In the diagnostic workup of patients with suspected PCa, mpMRI represents the second and probably the second most important step after one (or more) prior negative biopsies. In the literature, there is an overall consensus that mpMRI is useful in candidates for repeat biopsy and the detection rate for PCa in these patients ranges between 39% and 59%, with an incidence of cancer located only in the anterior zone of 20% (68-73). Porpiglia et al. demonstrated that mpMRI is significantly superior to PCA3 and PHI in predicting the outcome of a prostatic biopsy after an initial negative result (74). In a recent meta-analysis, mpMRI was shown to have the potential to accurately exclude significant PCa and reduce biopsy burden (29). Fourteen articles reporting the outcomes of 15 studies were included. Valerio et al. reported that TPBx detected more clinically significant PCa (median: 33.3% vs. 23.6%; range: 13.2-50% vs. 4.8-52%) using fewer cores (median: 9.2 vs. 37.1) compared with SPBx, respectively. Some studies showed a lower detection rate of all cancer (median: 50.5% vs. 43.4%; range: 23.7-82.1% vs. 14.3-59%). TPBx was able to detect some clinically significant PCa that would have been missed by using only SPBx (median: 9.1%; range: 5-16.2%). Fusion TPBx detected more clinically significant PCa than visual-cognitive TPBx in the only study reporting this outcome (20.3% vs. 15.1%).

Cash et al. showed that detection of clinically significant PCa is correlated with the PIRADS score (32). Their analysis included 408 consecutive men who underwent TPBx and 10-core SPBx. The overall cancer detection rate was 56% (227/408). The cancer detection rates correlated with PIRADS 2, 3, 4 and 5 and were 16% (5/32), 26% (29/113), 62% (94/152) and 89% (99/111), respectively. They concluded that cancer detection rate was strongly correlated with a rising PIRADS score, values of 4 and 5 increasing the detection of clinically significant PCa and leading to a higher histological stage after surgery.

The results described above are supported by the high negative predictive value of mpMRI on a patient-by-patient basis and a sufficient accuracy on a lesion-by-lesion basis. Nonetheless, current reported figures for the negative predictive value for mpMRI range from 60% to 100% (29); this wide range is due to the lack of standardized criteria for reporting mpMRI results, defining clinically significant PCa, population features, analysis methods and, last but not least, radiologist expertise, between different studies. The reliability of a negative mpMRI is a key clinical metric. It is, therefore, important for an mpMRI to accurately exclude tumor, and a low false-negative rate is a key determinate of whether this approach is clinically feasible.

The Committee has defined the mandatory technical requirements and the reporting system that should always be adopted (74). In particular, it is suggested to report the detection and measurements of all abnormal prostatic lesions with the identification of the index lesion, the localization of the lesion according to the Dickinson scheme, and the probability of extraprostatic extension. The suspicious lesions should be scored according to the PIRADS v.2 system (74-76).

The Committee concluded that mpMRI is necessary in most cases after an initial negative biopsy, and a TPBx (cognitive or software-based, as well as fusion) should be performed in case of PIRADS 4 or 5. TPBx in PIRADS 3 foci may be considered according to clinical parameters. The expertise of the radiologist in the interpretation of mpMRI seems to be a key factor.

3 Number of cores to be taken when performing a biopsy

Recommendation 3: At least 12 cores should be taken in each patient plus targeted (fusion or cognitive) biopsies on suspicious area [at mpMRI or transrectal ultrasound (TRUS)]. Saturation biopsies are optional in all settings. Both peripheral and anterior zone should be always sampled.

Optimizing PCa detection rate in clinical practice translates into defining the ideal number and location of biopsy cores to maximize detection of clinically significant PCa, minimize detection of clinically insignificant PCa, and reduce the necessity for repeat biopsy. The SPBx scheme (sextant template plus laterally directed sampling from each sextant template) has become the most widely accepted method in the initial procedure (15, 77-80). Some authors emphasize the need to sample the apical and far-lateral regions as these appear to increase the detection rate for PCa. However,transition-zone sampling does not improve PCa detection at initial biopsy (78-81). In candidates for surgery for benign prostate hyperplasia (i.e. prostate laser vaporization), prostate biopsies of the anterior zone are recommended even if not mandatory. A potential drawback of increasing the core number at the time of initial prostate biopsy is the increased likelihood of detecting insignificant PCa, especially when sampling the anterior region of the prostate.

The panel of experts did not support the recommendations to use saturation biopsy (≥20 cores) in biopsy naive men even if they suggested to consider more aggressive scheme than the classical extended 12-core scheme. However, the number and location of cores may vary according to some modulatory factors such as prostate volume (≥60 cc), patient features (i.e. age, comorbidities etc.), suspicious areas on imaging. The search for and targeting of hypoechoic lesions on TRUS remain controversial but, nowadays, only suspicious areas at mpMRI (in particular area classified as PIRADS 4 or 5) have been demonstrated to have a high degree of correlation with clinically significant PCa and can be used to define a targeted area before prostate biopsy (82).

A repeat biopsy strategy may include extended prostate biopsy (>12 cores), saturation biopsy, or image (mpMRI) guidance to improve the detection rate (15, 82). Overall, when performing repeat prostate biopsy, it is mandatory to increase the number of cores compared to the initial setting (82); moreover, it is important to recognize that regions of the prostate such as the anterior apex, the peripheral midline and far anterior zone are under-sampled at initial biopsy (77-80). Saturation prostate biopsy may be considered in men with a prior negative biopsy and persistent suspicion of prostate cancer. Nowadays, it is advisable to use TPBx for the repeat session, indeed, it has the potential to reduce the sampling error through localization of disease, increasing the detection of clinically significant PCa.

The optimal technique for TPBx is still a matter of debate. Two recent trials compared the diagnostic accuracy of software-based biopsy to cognitive (visual) biopsy and failed to detect a significant difference in the overall detection of clinically significant PCa (83-84). Nevertheless, the Committee did consider that there may be some differences in the respective abilities of these techniques to detect PCa in different locations of the prostate.

4 Biopsy approach and technique

Recommendation 4a: Transrectal and transperineal prostate biopsy procedures are recommended with the same level of evidence.

Although the majority of the Urological Centers perform biopsy via the transrectal approach, in recent years, the transperineal prostate biopsy has gained popularity due to its lower incidence of sepsis (71), higher detection rate for anterior PCa (15-20% of the cases) and the opportunity to perform template-guided prostate biopsy (85-87). Transrectal and transperineal prostate biopsy procedures are recommended with the same level of evidence (76) and provided a similar detection rate for PCa in initial (34%-40%) and repeat procedures (22-43%) with at least 12 (extended biopsy) and 20 (saturation biopsy) cores, respectively (85-87) (Table I).

Recommendation 4b: The Committee has recommended extended biopsy schemes be combined with TPBx in the reclassification of men under active surveillance.

The prostate biopsy is the gold standard in the reclassification of men enrolled in active surveillance. Confirmatory repeat biopsy, which is generally performed after 1 year of enrollment, is the most important instrument to define unfavorable quantitative histological results (25-30% of the cases) and probably progression (i.e., Gleason score >6, number of positive cores >2, greatest percentage of cancer >50%) (88-90). The optimal number of biopsy cores (extended vs. saturation vs. template-guided schemes) and biopsy approach (transrectal vs. transperineal) have not been established, while the transperineal biopsy seems more accurate at identifying the PCa risk class of the patients enrolled in active surveillance protocols (88-90). The committee has recommended to perform extended (or even saturation prostate) biopsy schemes combined with TPBx in order to obtain the highest accuracy in diagnosing csPCa in the reclassification of men in active surveillance. Finally, transperineal prostate biopsy greatly reduces the incidence of sepsis (strong recommendation) secondary to antibiotic resistance (range: 0-0.07% of cases), which in men submitted to a transrectal approach could reach 1-2.5% of the cases (88-90).

5 How to reduce infections

Recommendation 5: In men at high risk of sepsis (i.e. recurrent prostatitis, recurrent urinary tract infection, hospitalization), rectal culture or transperineal approach are strongly recommended. Changing or use of double antibiotic drugs is optional.

Clinical complications and hospital admissions following prostate biopsy have increased during the past 10 years primarily due to an increasing rate of infection (87). Although antibiotic prophylaxis following prostate biopsy is mandatory, there are no definitive data to confirm that long-course (>3 days) are superior to short-course antibiotic treatments (1 day) (87); in order to achieve an optimal therapeutic level of antibiotic, the drug should be administered 2-3 hours prior to the biopsy. The risk of sepsis following transrectal biopsy reached 1-2.5% of cases, mainly due to multidrug-resistant Escherichia coli (86, 91-92). To date there is no strong evidence for factors associated with infective complications; fecal carriage of fluoroquinolone-resistant E. coli strains represents a significant risk factor classifying patients into a high-risk group for infective complications after transrectal prostate biopsy (93).

Various strategies have been reported to reduce infectious complications. One strategy is rectal cleansing with povidone-iodine prior to transrectal biopsy, but this failed to reduce infection significantly (94). Many studies have investigated switching or expanding the antimicrobial regimen, performing rectal swab cultures and using different techniques for biopsy. Patients with ciprofloxacin-sensitive bacteria can then receive ciprofloxacin prophylaxis, while culture results can guide an alternative selection for those with resistance. Although a positive rectal swab culture is a risk factor for infection after transrectal biopsy, the presence of resistant organisms does not necessarily translate into clinical infection. Most studies have shown that there is no evident superiority in antibiotic prophylaxis and its disadvantages, such as possible increase in side-effects, cost effectiveness and the drawback of increasing future antimicrobial resistance are of great concern (94-96). It is noteworthy that according to recent randomized trials, fosfomycin before transrectal prostate biopsy led to a lower rate of infective complications when compared with standard therapy with fluoroquinolone drugs, thus representing a strong alternative for antibiotic prophylaxis, in particular in populations where fluoroquinolone resistance is common (98). To date, there are no randomized studies showing that targeted prophylaxis using rectal swabs reduces infection and cost compared with standard or expanded prophylaxis. In clinical practice, enema containing iodine-povidone or clorexidine is used in most centers using the transrectal approach. Even if weak scientific evidence supports this procedure, an antibacterial enema performed immediately before transrectal biopsy is recommended according to expert opinion.

The Committee stated that all men undergoing transrectal prostatic biopsies should receive antimicrobial prophylaxis, should be warned about the increasing risk of infection, and told to seek prompt medical care in case of signs of systemic infection. In men at risk of sepsis (i.e. those with recurrent prostatitis, recurrent urinary tract infection, prior hospitalization for sepsis at initial biopsy) culture based on rectal swab or transperineal approach are suggested.

6 How to optimize prostate biopsy preparation in order to reduce complications

Recommendation 6: In order to reduce risk of bleeding, when possible, anticoagulant or anti-aggregant drugs should be stopped 7 days before biopsy.

Biopsy is typically well tolerated, with a low risk of major complications. However, minor complications such as bleeding and pain are frequent.

One of the most frequent and bothersome complications of transrectal biopsy is bleeding (87), such as hematuria, hematospermia, and hematochezia, or rectal bleeding.

One contentious area is the discontinuation of anticoagulant therapy before biopsy, which involves a balance of risks between cardiovascular or thromboembolic events when stopping anticoagulation versus the risk of bleeding and associated complications with continuation. Various reports have described bleeding complications in men taking warfarin and aspirin.

A systematic review and meta-analysis of aspirin use and bleeding following transrectal biopsy found higher rates of hematuria with use of anticoagulant. In total, 3218 men were identified in reports from 1990-2011, and the risk of hematuria increased 1.36-fold with aspirin use (99-100). Rectal bleeding and hematospermia were not statistically increased. The authors concluded that continuing aspirin did not increase the risk of moderate and severe hematuria after transrectal biopsy, thus stopping aspirin is unnecessary.

Giannarini et al. prospectively assigned 196 men to continue aspirin, replaced it with low molecular-weight heparin or discontinued aspirin without replacement for transrectal biopsy. There was no difference in the overall bleeding rate among groups. Although no severe bleeding complications occurred, men on anticoagulant reported bleeding for a longer duration. The authors concluded that aspirin did not increase mild bleeding but did prolong its duration (101).

The Committee concluded that whenever possible, anticoagulant or anti-aggregant drugs should be stopped 7 days before the procedure (102).

Local anesthesia using 10 mg of lidocaine to perform the periprostatic block is, nowadays, mandatory. In the case of transperineal saturation, template biopsy or fusion procedure, locoregional or even general anesthesia are recommended.

7 Pathological issues

Recommendation 7: If the length of the fresh specimen is less than 1 cm, one more biopsy core in the same sampling is recommended. Biopsy specimens should be collected single or grouped (no more than 2 or 3), labeled separately per zone (base, mid, apex, anterior zone) and collected by pre-embedded sandwich technique. The new definition of grading patterns for PCa suggesting five prognostic grade groups should always be adopted in addition to the Gleason scoring system.

The average length of prostatic tissue per biopsy core should be >10 mm, if the length of the fresh specimen is less, one more biopsy core in the same sampling is recommended. Biopsy specimens should be collected as single or grouped (no more than 2 or 3), labeled separately per side (right and left) and area (base, mid, apex, anterior zone) and collected by pre-embedded sandwich technique (103). Recently, the International Society of Urological Pathology (ISUP) stated a new definition of grading patterns for Prostate cancer suggesting five prognostic Grade Groups. The new grades would, for the foreseeable future, be used in conjunction with the Gleason system (i.e. Gleason score 3+3=6, Grade group 1). The new grading system and the terminology Grade Groups 1-5 have also been accepted by the World Health Organization (appendix I-III) (104).